JPS6130674B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to hexahydro-trans-pyridindole neuroleptics. The success of treating schizophrenic behavior with antipsychotic tranquilizers such as chlorpromazine has spurred research to find other neuroleptic agents with improved biological properties. One such class of compounds are the 2,3,4,4a,5,9a-hexahydro-1H-pyrido[4,3-b]indoles. The basic ring structure is It is. The principal chemistry at positions 4a and 9b of the hexahydro system can be cis or trans, each of which can exist in racemic (±) or enantiomeric (+ or -) form. tranquilizers, neuroleptics, analgesics, sedatives,
Examples of hexahydro-pyridoindoles useful as muscle relaxants and hypotensive agents are shown in the following U.S. patents: U.S. Pat. No. 3,687,961; U.S. Pat. No. 3,983,239; U.S. Pat. No. 4001263; U.S. Patent No. 4141980; and U.S. Patent No. 4224329. Potent neuroleptic activity is now substituted with an aryl group in the 5-position and an aminoalkyl or carbonylaminoalkyl group in the 2-position (this carbonyl group can also be substituted with hydrogen, alkyl,
substituted with an aryl, aralkyl or alkoxy group; or an alkano group [-
(CH ₂ ) _i - (where i is 3 to 5)] or carbonyl, alkano, alkeno (-CH=
CH-), O-benzeno

Novel 2.3・4・4a・5・9b-hexahydro-4a・
It was discovered for 9b-trans-1H-pyrido[4,3-b]indoles. The neuroleptic agent of the present invention has the formula [In the formula, n is 2 to 6, and R ¹ is

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【formula】 or

The (+) enantiomer, the mixture of (+) and (-) enantiomers, or the (±) racemate of [formula],
4a.9b-trans-hexahydro-1H-pyridoindole derivative or a pharmaceutically acceptable salt thereof. The compounds of the invention can be used to prepare pharmaceutically acceptable salts of the compounds defined above, pharmaceutical compositions of these compounds, and by the oral or parenteral (intravenous, intramuscular or subcutaneous) route. A method of treating psychosis and neurosis in patients in need of greater mental stability is obtained by administering to the patient an effective amount of one of the compounds of the present invention, either alone or as a component of a pharmaceutical composition. An example of R ¹ in formula (A) is: 2-piperidon-1-yl 2-oxazolidinon-3-yl 2,3-dihydro-2-benz[d]oxazolon-3-yl 2,3-indolinedione-1-yl 1,1-dioxo-3(2H)-benz[d]isothiazolon-2-yl 2,3-dihydro-2,3(1H)-isoindoldione-2-yl 2,4-thiazolidinedione-3-yl 2,4-Imidazolidinedione-3-yl The compounds of the present invention are readily prepared by the methods detailed in the next section. For discussion, this 2, 3, 4, 4a, 5, 9b-hexahydro-
4a・9b-trans-1H-pyrido [4・3-b]
indole nucleus will be denoted as R. Compounds of the present invention contain three reactants: (a) (±)RH or (+)RH; (b) an alpha, omega di-substituted linear alkane (or alkane precursor); and (c) a side chain end group. , or terminal precursor. It can be considered that it can be synthesized from 2-piperidon-1-yl derivative [formula, p=
1, Z = methano group, A = ethano group; formula, R ⁵ and R ⁶ together are (CH ₂ ) ₃ CO] some basic methods applied. explain. Method A: (a) + (b) (c) → (a) (b) (c) where n and R are as defined above;
D represents a substitutable group (Cl, Br, I, CH ₃ SO ₂ O, etc.). This nucleophilic substitution reaction is performed on lower aliphatic ketones (e.g. acetone, 2-butanone, 3
- Inert to the reaction, such as methyl-2-butanone, 3-methyl-2-pentanone), lower alkanols (e.g. ethanol, 2-propanol), or lower aliphatic amides (e.g. dimethylformamide, dimethylacetamide) carried out in a suitable solvent. Pyridoindole (RH) is preferably prepared by adding at least one equivalent of a base, such as sodium carbonate, to the reaction mixture.
It is kept in the free base form, which is much more reactive. When D is other than I, iodide ions can be added to increase the reaction rate, if desired. Temperature is not critical and temperature is usually increased (e.g. 50-150°C) to increase reaction rate
but not so high as to cause undesirable temperature decomposition of the products and/or reactants. The pyrido[4,3-b]indole compounds required for these syntheses and further syntheses detailed below are described in U.S. Pat. No. 3,687,961;
No. 3983239; No. 3991199; No. 4001263; No.
4141980 and 4224329. Piperidone derivatives are composed of a 2-piperidone anion and a disubstituted alkane, D(CH ₂ ) _o D, where D and n are as defined above and the two D groups are the same or different. (can be)
It can be easily obtained by reaction with Bis-substitution can be achieved by using an excess of D(CH ₂ ) _o D and/or by one group being more easily substituted [e.g. Cl(CH ₂ ) _o Br] is reduced as much as possible. The reaction conditions (solution and temperature) were as follows, except that protic solvents that are more acidic than 2-piperidone (e.g., alcohols) were avoided.
Generally as described above. The same method is widely applicable for the synthesis of many other compounds of the invention. If the side chain terminal substituent is a group such as a benzyl group, the side chain terminal substituent can be removed by hydrogenolysis, leaving the terminal unsubstituted piperazino group, e.g. is obtained. Method B: (a)(b)+(c)→(a)(b)(c) where R, n and D are as defined above. This nucleophilic substitution uses substantially equivalent amounts of reactants, or if

It is carried out under conditions as described above for the synthesis of formula. Although substituted pyrido[4.3-b]indole compounds are potentially obtained by many routes, the preferred route is; It is. The piperidone anion is generally formed in situ by reaction of piperidone with sodium hydride. Method C: (a)(b)(c)→(a)(b)(c) where R and n are as defined above, and x and y are each greater than or equal to 1, and x+y-2=n. These are hydrogenation reactions which are carried out in an inert solvent under a hydrogen atmosphere in the presence of a hydrogenation catalyst, which is preferably a hydrogenation catalyst known in the art such as oxides, chlorides, etc. Like the catalytic compounds are noble metal catalysts including platinum, palladium, rhodium and thenium, in supported or unsupported form. Specific examples of suitable catalysts are 5% palladium on carbon, 5% palladium on barium carbonate, 5% rhodium on carbon, rhodium chloride, platinum oxide and ruthenium on carbon. The temperature and pressure of the hydrogenation is not critical, but it is usually carried out at pressures ranging from subatmospheric to 100 atmospheres or more, and at temperatures in the range 10-90°C, conveniently 20-50°C. . A convenient operating pressure is 2-3 atmospheres. The starting materials required for these syntheses are generally D(CH ₂ ) _o D replaced by an unsaturated compound,
Following method A above, e.g. It can be obtained by Alternatively, the following synthetic routes are available; The first stage nucleophilic substitution reaction is carried out under the conditions described above. The second step, formaldehyde cross-linking of acetylene to RH, consists of RH in free base form, an equal amount of formaldehyde (conveniently as a 30% aqueous solution) and an equal amount of formaldehyde in the presence of cuprous chloride as a catalyst. It is carried out using acetylene in a reaction active solvent (lower alkanols are particularly suitable). Although temperature is not critical (e.g. 0-50°C), reactions are conveniently carried out at ambient temperatures (20-25°C).
℃). This method can also be applied to the synthesis of many other compounds of the invention when the terminal ends do not contain groups susceptible to significant hydrogenation side reactions under the conditions used for hydrogenation of unsaturations. In the case of benzyl protecting groups, this can usually be removed during the same reaction as the reduction of the unsaturated group. for example, When the terminal does not contain a carbonyl group, hydride reduction of the amide precursor leads to the compounds of the invention. for example, Yet another variation is to reduce different terminal amide groups separately or simultaneously, e.g. It is. These hydride reductions are conveniently carried out in excess of lithium aluminum hydride (2 equivalents for each amide function) in an ethereal solvent (e.g. diethyl ether, tetrahydrofuran, dioxane) at a temperature range of 0-50°C. (required). Alternatively, such amides are reduced with diborane or aluminum hydride in the same type of solvent, or reacted with triethyloxonium fluoroborate (e.g. in methylene chloride at 20-30°C); It is then reduced with sodium borohydride in a lower alkanol (e.g. ethanol) at 0-25°C. Method D: (a)(b)(c)→(a)(b)(c) where n, R and D are as defined above and ^R7 is a ( _C1 - _C5 ) alkyl group.
Nucleophilic substitution of D is carried out under the conditions detailed above. Anions can be preformed or formed in situ using a strong base such as sodium hydride. The intermediate is conveniently derived by acylation of the amine: This intermediate amide need not be isolated, but
However, it is formed in situ and can then be converted into an anion. Acylation is carried out under mild conditions (e.g. -25 to 35°C), usually with at least one equivalent of an inorganic base or a tertiary amine (e.g. triethylamine, N-methylmorpholine).
The reaction is carried out in a solvent that is inert to the reaction in the presence of. Another step, cyclization of the amino ester precursor, is carried out using a solvent inert to the reaction, conveniently benzene,
This is achieved by simply heating the amino ester in free base form in an aromatic hydrocarbon such as toluene or xylene. Temperature is not critical for the reaction to proceed at a reasonable rate (eg, 80-150°C, preferably 100-125°C), but temperature-induced decomposition is minimized. The preferred R ⁷ is a methyl group since cyclization occurs most rapidly at the lowest possible temperature. Amino ester is
Alkylation of amines: or reductive amination of aldehydes: conveniently manufactured by. In a modified form, the reaction just described can be used for the preparation of other compounds of the invention, e.g. (wherein R and R ⁶ are as defined above, n is 2 to 9, m is 2 to 6, R ⁴ is H,

[Formula]-CH ₂ C ₆ H ₅ ). Pharmaceutically acceptable salts of this derivative can be prepared by reaction with either about 1 molar equivalent or about 2 molar equivalents of an organic or mineral acid in aqueous or non-aqueous solution. The compounds of the present invention are generally dibasic, thereby forming either mono- or bis-salts, depending on the molar equivalent of the acid. Tribasic compounds can of course form Tris salts, in which case 3 molar equivalents of acid can be used. Acids that form suitable salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,
Included are p-toluenesulfonic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid and gluconic acid. This salt can be removed by removing the solvent in vacuo or
or by sinking, as appropriate.
can be isolated. These derivatives are useful as neuroleptics in the treatment of mental disorders and diseases, including schizophrenia, psychoses and neuroses. Symptoms requiring such treatment include anxiety, aggression, agitation,
Includes depression, hallucinations, nervousness and emotional or social autism. In general, this derivative exhibits better psycholeptic activity than currently used drugs, but with fewer side effects. This derivative can be used in various pharmaceutical formulations containing the derivative alone or in combination with pharmaceutical carriers such as inert solid diluents, aqueous solutions or various non-toxic organic solvents, and as gelatin capsules, tablets. They can be formulated in dosage forms such as powders, lozenges, syrups, injections, and the like. Such carriers include water, ethanol, gelatin, lactose,
Included are starch, vegetable oils, petrolatum, gums, glycols, talc, benzoyl alcohol, and other known drug carriers. If desired, these pharmaceutical formulations can contain preservatives, stabilizing agents, wetting agents, buffering agents, and tonicity agents. The derivatives are administered to patients in need of treatment by a number of conventional routes of administration, such as orally, intravenously, intramuscularly or subcutaneously. Generally, small doses will be administered initially and the dosage will be increased gradually until the optimal level is determined. However, as with all drugs, certain doses,
Prescription and route of administration will vary with the age, weight and responsiveness of a particular patient and will depend on the judgment of his attending physician. In the normal course of treatment, approximately 0.1 per day
Doses of mg to 100 mg of derivative will provide effective treatment in human patients. When the derivative has a prolonged effect, the dosage can be administered less frequently, such as every other day or in one or two divided doses per week. The psycholeptic activity of this derivative can be determined using well-known standard procedures - antagonism of amphetamine-induced symptoms in rats. This method has an excellent correlation with efficacy in humans, and was developed by A.
Weissman), J.Pharmacol.Exp.Ther.151, No.
Page 339 (1966) and Quinton et al., Nature 200, page 178,
(1963), and more specifically, Herbert et al., Molecular
Pharmacology 17, pages 38-41 (1980). In detail, the in vivo neuroleptic effect is
Estimated interference with amphetamine stereotypy. Rats were individually placed in covered plastic chambers; after a short period of acclimatization in the cage, rats were divided into five groups, each receiving a dose divided by 0.5 log increments (i.e.,...1, 3.2, 10, 32,
... mg/Kg) of the test compound was used for intraperitoneal treatment. They were sequentially treated with d -amphetamine sulfate 5 mg/Kg intraperitoneal injection after 1, 5, and 24 hr. One hour after each amphetamine challenge, each rat was rated for its most characteristic cage behavior on a 6-point scale.
Pages 339-352 (1966)]. These grades indicate the increasing degree of effectiveness of the drug (Quinton).
and Halliwell, Nature
(London) 200, pp. 178-179 (1963)], and the time of the chosen magnitude is consistent with the peak effect of amphetamine [Weissman, Psychopharmacologia 12, 142
−157 pages, (1968)]. Scores were dichotomized (see Weissman et al., same article, same page), and an approximate ED ₅₀ was determined based on quantitative samples. The dosage is expressed in terms of hydrochloride. As illustrated by the results shown in Table 1, this method shows that the compounds of the invention have superior tranquilizing activity compared to the standard test drug chlorpromazine. The so-called "inherent" psycholeptic neuroleptic activity of this class of derivatives has been demonstrated by Leysen et al.
Biochem.Pharmacol.27, page 307 (1978),
was determined using ^3H -spiroperidol binding to dopamine receptors according to the method of Burt et al., Mol. Pharmacol, 12, No. 800-812.
Adapted from the method of Page (1976). Rats (Sprague-Dawley, Charles River Research Institute, Wilmington, Mass.)
CD males (250-300 g) were decapitated, the brain was immediately dissected, and the striatum was collected. The latter was homogenized in 40 volumes of ice-cold 50 mM Tris (tris[hydroxymethyl]aminomethane).HCl buffer at pH 7.7 using a Brinkmann Polytron PT-10. The homogenate was rehomogenized with intermediate crystal globules in fresh Tris buffer (equal volumes) in a Polytron and centrifuged twice at 50,000 g for 10 minutes at 0-4°. The final crystal globules were washed in 120mM NaCl, 5mM KCl, 2
PH containing mM CaCl ₂ , 1 mM MgCl ₂ , 0.1% ascorbic acid, and 10 μM pargyline.
Gently resuspend in 50 volumes of cold 50mM Tris-HCl buffer at 7.6. The tissue suspension was placed in a 37° water bath for 5 minutes and kept on ice until use. The incubated mixture contained 0.02 ml of inhibitor solution or excipient, 1.0 ml of tissue preparation and 0.10 ml adjusted to a final concentration of 0.5 nM.
³ H-spiroperidol (New England Nuclear, 23.6 C;/mmol). Divide the tubes into three groups and incubate them continuously at 37° for 10 minutes, then add 0.9ml from each tube.
was vacuumed and filtered through a Wurtmann GF/B filter. After washing twice with 5 ml of cold Tris HCl buffer at pH 7.7, each filter was placed in a scintillation vial with 10 ml of Aquasol-2 (New England Nuclear) and each vial was vortexed. Samples were kept at room temperature overnight before determination of radioactivity in a liquid scintillation counter. Binding was calculated as femtomoles of ³ H-spiroperidol bonds per milligram of protein. Controls (vehicle or 10 ^-7 M1-butaclamol), blanks (10 ^-7 M d-butaclamol) and inhibitor solutions (4 concentrations) were run in triplicate. The concentration that reduces binding by 50% (IC ₅₀ ) was estimated on semi-log paper. The IC ₅₀ values in the table represent the average of 2 or 3 results. Insoluble drugs were dissolved in ethanol (1-2% ethanol in the final incubation mixture). As shown in the table, this unique method shows that the compounds of the present invention have excellent neuroleptic activity. The invention is illustrated by the following examples.
However, it should be understood that the invention is not limited to the specific details of these examples. The relationship between the example numbers and their products is shown in the table below.

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[Table] Reference example 1 1-(4-chloro-1-butyl)-2-piperidone Sodium hydride (3.87 g of 50% dispersion in oil,
0.0807 mol) was suspended in 80 ml of dry dimethylformamide and stirred. 1,4-dichlorobutane (44
ml, 0.404 mol) and 2-piperidone (8 g,
A solution of 0.0807 mol) was added dropwise over a period of 1 hour, maintaining the temperature at 25-30°C by using a water bath. After stirring the reaction mixture at room temperature for 16 hours, the by-product salts were removed by filtration and the mother liquor was evaporated to one-tenth the volume in vacuo.
The concentrate obtained in this way was mixed with 100 ml of water and 100 ml of hexane.
distributed between. Separate the lower oily phase of the three phases and dilute with 50 ml of methylene chloride.
Dry over magnesium sulfate, filter and evaporate to give 1-(4-chloro-1-butyl)-
2-piperidone was obtained as an oil [14.3 g;
pnmr (CDCl ₃ ) delta 1.4−1.83 (4H, m), 3.03
−3.72 (6H, m), 4.10−4.43 (2H, t, J=
7)]. Example 1 (+)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2.3.4.4a.5・9b
-hexahydro-4a.9b-trans-1H-pyrido[4.3-b]indole hydrochloride Method A 1-(4-chloro-1-butyl)-2-piperidone (496 mg, 2.62 mmol), (+)- 8-Fluoro-5-(4-fluorophenyl)-2, 3, 4,
4a, 5, 9b-hexahydro-4a, 9b-trans-1H-pyrido [4, 3-b] indole (500
mg, 1.75 mmol), anhydrous sodium carbonate (1.1
g, 10.4 mmol) and potassium iodide (5
mg) were combined in 3-methyl-2-butanone (20ml) and the slurry was refluxed for 16 hours. The reaction mixture was evaporated to a solid in vacuo and the residue was partitioned between 50ml methylene chloride and 50ml water. The aqueous layer was washed with 50ml of fresh methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to a gum. This gum was chromatographed on silica gel using 1:10 methanol:ethyl acetate as eluent and TLC testing. The clear, product-containing fractions were combined and evaporated to yield a second gum. This second rubber is dissolved in methylene chloride,
The hydrochloric acid addition salt was converted by adding ethereal hydrogen chloride and the mixture was reevaporated to a foam. This foam was slurried with 50 ml of ether and filtered to give the title product [532
mg, Rf0.4 (1:4 methanol:ethyl acetate):
ir (KBr) 1215, 1468, 1503, 1605, 2924, 3394
cm ^-1 ]. Reference example 2 (+)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-2-butyn-1-yl]-2.3.4・
4a, 5, 9b-hexahydro-4a, 9b-trans-1H-pyrido[4,3-b]indole Sodium hydride (5.76 g of 50% dispersion in oil,
0.12 mol) was washed three times with hexane and suspended in 645 ml of toluene. 2-Piperidone (11.88 g, 0.12 mol) in 100 ml of toluene was added to the well-stirred sodium hydride suspension and heated to reflux for 2 hours. The reaction mixture was cooled to 15°C and 2-propynyl bromide (14.28g, 0.12mol) in 55ml toluene was added over 30 minutes. The mixture was then stirred at room temperature for 19 hours, filtered and
Evaporation of the mother liquor yields 1-(2-propynyl)-2
- The first batch of piperidone was obtained as an oil (7.87 g of approximately 55% purity by pnmr analysis). In the second run, the amount of sodium hydride dispersion was increased to 7.2 g and suspended in 500 ml of tetrahydrofuran instead of toluene. For isolation,
The reaction mixture was mixed with concentrated hydrochloric acid (17 ml, 0.20 mol) and ice.
Pour carefully onto the mixture with 300ml. The reaction mixture after the reaction was completed was extracted with 3 parts of ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to give 1-
A second batch of (2-propyl)-2-piperidone (13 g of approximately 50% purity by PNMR analysis) was obtained. (+)-8-Fluoro-5-(3-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4.3-b]indole hydrochloride ( (11.0 g, 34.2 mmol) was converted to the free base by partitioning between ethyl acetate and excess dilute sodium hydroxide. The ethyl acetate layer was separated, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The rubber thus obtained was dissolved in 450 ml of absolute ethanol. Formaldehyde (30% aqueous solution 3.41
ml, 34.2 mmol) and stirred the solution.
Warmed to 35℃. Cuprous chloride (5.1 g) was added followed by a mixture of the first and second batches of 1-(2-propynyl)-2-piperidone (4.67 g, 34.2 mmol by analysis). The suspension thus obtained was heated to room temperature.
Stirred for 18 hours. The reaction mixture was filtered and
Washed with ethanol to clarify and the combined filtrate/washings evaporated to a gum. Add this rubber to as little volume as possible of 9:1 ethyl acetate:
Silica gel 650 dissolved in methanol and examined by TLC using first ethyl acetate followed by 9:1 ethyl acetate:methanol as eluent.
Chromatographed on g.g. The clear intermediate cuts were combined and evaporated to dryness to give the title product [12.5
g, Rf0.75 (1:10 ethyl acetate:methanol)]
was obtained in its free base form. A portion (0.5 g) of this free base was dissolved in 50 ml of ether. The stirred solution was saturated with hydrogen chloride and left for 2 days. The title product was recovered as a crystalline solid by filtration. [247 mg, melting point 123-125°C, [Alpha] ²⁵ _D = +13.78° (methanol, C = 0.73)]. Analysis: _C26H27ON3F2・_HCl・_{1.5H2O Calculated} value: C, 62.57; H, _6.26 ; N, 8.42 Actual value: C, 62.37; H, 6.25; N, 8.20 Example 2 (+)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2.3.4.4a.5.9b
-hexahydro-4a.9b-trans-1H-pyrido [4.3-b-indole (Method B) Compound of Reference Example 2 in free base form (12.4 g)
was dissolved in 270 ml of absolute ethanol. Catalyst (5% Pd/c, 3g) was added and the mixture was heated at room temperature.
Hydrogenation was carried out for 90 minutes, during which time the hydrogen consumption ended. The catalyst was recovered by filtration and the filtrate was evaporated to give a rubber. This rubber was used as an eluent in 9:
Chromatographed on 250 g of silica gel using ethyl acetate:methanol and checked by TLC. The fractions containing the clear product were evaporated to give the title product [8.6 g, Rf 0.3 (9:1 ethyl acetate:methanol); [Alpha] ²³ _D = +15.8
(methanol, C=0.5)] was obtained as the free base. The free base (87 mg) and benzenesulfonic acid (35mg) gave the title product, the benzenesulfonate salt (84mg, mp 138-141°C). Similarly, from free base (85 mg) and benzoic acid (26 mg),
The benzoate salt (melting point 42-44°C) was obtained, and also from maleic acid the maleate salt (melting point approximately 80°C). Example 3 (+)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2.3.4.4a.5・9b
-hexahydro-4a.9b-trans-1H-pyrido[4.3-b]indolbis(dihydrogen phosphate) The title compound in free base form (7.2 g, 16.4 mmol) was dissolved in 200 ml of ethyl acetate. I let it happen. With vigorous stirring, phosphoric acid (3.76 g of 85.5%, 32.8 mmol) in 20 ml of ethyl acetate was added dropwise, and the desired salt precipitated in the form of a crude product (12 g). 50ml of methanol boiling this crude product
dissolved in it. Ethyl acetate (50ml) was added and the mixture was slowly cooled to room temperature. The purified title product was collected by filtration and dried in vacuo over phosphorus pentoxide (8.49 g, mp 197-8°C; [Alpha] ²³ _D = +16.61°). Analysis: _Calculated value as _C26H31ON3F2・( _H3PO4 ) ₂ : C, 49.14; H, _5.87 ; N, 6.62 Actual value _: C, 48.93; H, 5.84; N _, 6.68 Reference example 3 1-(6-bromo-1-hexyl)-2-piperidone Sodium hydride (3.63 g of 50% dispersion in oil, 0.15 mol), 1.6-
Dibromohexane (23.07ml, 0.15mol) and 2-piperidone (7.5g, 0.076mol) were reacted in dimethylformamide. The filtered and concentrated reaction mixture was dissolved in 200ml water and 200ml hexane. The hexane layer was separated and evaporated to an oil. This oil was chromatographed on silica gel using ethyl acetate as eluent and TLC testing. The clear, product-containing fractions were combined and evaporated to give 1-(6-bromo-1-hexyl)-2-piperidone to an oil (3.66
g) was obtained. Example 4 (±)-8-fluoro-5-(4-fluorophenyl)-2-[6-(2-piperidon-1-yl)-1-hexyl]-2.3.4.4a.5・
9b-hexahydro-4a・9b-trans-1H-
Pyrido[4.3-b]indole hydrochloride (Method A) By the process of Reference Example 1 doubled in scale, 1
The free base of the title product was prepared in crude form from -(6-bromo-1-hexyl)-2-piperidone. Purification was carried out by chromatography on silica gel using 1:9 methanol:ethyl acetate as eluent. The title product was obtained as a solid (1.4 g) by combining the product fractions, diluting with excess ethereal hydrogen chloride, and evaporating.
obtained as. Melting point 235-238℃. Analysis: _C28H35ON3F2・_{HCl ・0.75H2O Calculated value} : C, 64.97; H, 7.34; N, 8.11 Actual value: C, 64.84; H, 7.04; N, 7.96 Reference example 4 8-Fluoro-5-(4-fluorophenyl)-
2-(3-cyano-1-propyl)-2.3.
4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole 8-fluoro-5-(4-fluorophenyl)- in methyl isobutyl ketone (40 ml) 2・3・
4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]-indole (1 g, 3.49 mmol), 4-bromobutanenitrile (0.723 g, 4.88 mmol), carbonic anhydride A stirred suspension of sodium (2.1 g, 20.9 mmol), potassium iodide (0.289 g, 1.74 mmol) was refluxed under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The resulting white solid was mixed with water (40 ml) and chloroform (50 ml).
ml). The phases were separated and the aqueous phase was extracted with chloroform (50ml). The organic layers were combined, dried (MgSO ₄ ) and evaporated in vacuo to give a pale yellow oil. This oil was treated with hydrogen chloride gas in acetone (40 ml), filtered and washed with acetone (10 ml).
0.813 g (60% yield) of the above-titled nitrile intermediate
was obtained as a white solid, mp 245-249°C (HCl salt). Analysis: _Calculated value _{as C21H21N3F2}・_HCl : C, 64.67; H, 5.42; N, 10.77 Actual value: C, 64.38; H, 5.71; N, 10.71 Reference example 5 (+)-8 -Fluoro-5-(4-fluorophenyl)-2-(4-amino-1-butyl)-2.
3.4.4a.5.9b-hexahydro-4a.9b
-trans-1H-pyrido[4.3-B]indole hydrochloride A stirred suspension of lithium aluminum hydride (0.167 g, 4.4 mmol) in diethyl ether (35 ml) under nitrogen was added to reaction temperature
The nitrile intermediate from the previous example (0.781 g, 2.0 mmol) was added at a rate sufficient to maintain the temperature at 28-30°C (15 minutes). After stirring at ambient temperature for 4 hours, Glauber's salt (Na ₂ SO ₄ 10H ₂ O; 1.2 g, 4
(mmol) was added in portions over 10 minutes. The white solid was filtered and diluted with diethyl ether (10
ml) and the filtrate was evaporated in vacuo to give a pale yellow oil. Treatment of this oil with hydrogen chloride in ether (35 ml), filtration and washing with ether (20 ml) yielded 0.498 g (64%) of the title compound.
Yield), white solid, melting point 224-227℃ (HCl salt)
obtained as. Analysis: C ₂₁ H ₂₅ N ₃ F ₂・2.5H ₂ Calculated value as O・HCl: C, 53.28; H, 6.38; N, 8.87 Actual value: C, 52.98; H, 5.94; N, 8.66 Reference example 6 3-(4-chloro-1-butyl)-2-oxazolidinone Piper et al. [J.Het.Chem.4, No. 298
Page (1967)], sodium hydride (4.8 g of a 50% dispersion in oil, 0.1 mol) was washed with pentane and suspended in 20 ml of dimethylformamide. Then dimethylformamide
2-oxazolidinone (8.7 g, 0.10 mol) and 1,4-dichlorobutane (66 g, 0.52 mol) in 100 ml
mol) solution was added dropwise over 30 minutes while maintaining the reaction temperature at 25-30°C. The reaction was stirred at ambient temperature for 18 hours, then evaporated to an oil, which was dissolved in ethyl acetate, treated with activated charcoal, filtered over diatomaceous earth, and reevaporated in vacuo. , the title product was obtained as an oil. [16.5g, contaminated with mineral oil from incompletely washed sodium hydride; pnmr/
CDCl ₃ /delta: 0.67-1.0 and 1.03-1.4 (mineral oil), 1.4-1.83 (m, 4H), 3.03-3.72 (m,
6H), 4.10-4.43 (t, 2H)]. Example 5 (+)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-oxazolidinone-3
-yl)-1-butyl]-2.3.4.4a.5.
9b-hexahydro-4a・9b-trans-1H-
Pyrido[4,3-b]indole hydrochloride 1-(4-chloro-
1-Butyl)-2-oxazolidinone (0.93g,
5.2 mmol) and (±)-8-fluoro-5-
(4-fluorophenyl)-2.3.4.4a.5.
9b-Hexahydro-4a.9b-trans-1H-pyrido[4.3-b]indole (1.0 g, 3.5 mmol) was dissolved in 40 ml of 3-methyl-2- in the presence of sodium carbonate (1.46 g, 13.8 mmol). Reaction in butanone and without chromatography gave the free base of the title product in the form of a gum. This gum was converted into the hydrochloride salt by dissolving it in a mixture of 10 ml of 2-propanol and 10 ml of acetone and adding excess ethereal hydrogen chloride. The title product slowly crystallized and was recovered by filtration [1.02 g, Rf 0.65 (7:1 ethyl acetate:methanol,); ir (KBr) 1181, 1219;
1258, 1477, 1513, ^{1760cm -1} ]. Reference Example 7 3-(6-bromohexyl)-2-oxazolidinone 3.85 g of a dispersion of sodium hydride (50% in oil) in dimethylformamide (180 ml total), 0.0804 mol, according to the procedure of Reference Example 1. ), 1・6-
dibromohexane (24.5 ml, 0.16 mol) and 2
-Oxazolidinone (7.0 g, 0.0804 mol) was reacted and the reaction mixture was concentrated to one-tenth the volume. Hexane (200ml) was added, the salts were removed by concentration and the heavy, oily layer was separated from the filtrate. This heavy layer was chromatographed on silica gel using ethyl acetate as eluent and TLC testing. The clear, product-containing fractions were collected and evaporated to give the title product as an oil [1.59g; Rf0.5 (ethyl acetate)]. Example 6 (±)-8-fluoro-5-(4-fluorophenyl)-2-[6-(2-oxazolidinone-3
-yl)-1-hexyl]-2, 3, 4, 4a.
5,9b-hexahydro-4a,9b-,trans-1H-pyrido[4,4,3-b]indole hydrochloride 3-(6- Bromo-1-hexyl)-2-oxazolidinone (1.59 g, 63.5 mmol) and pyridindole (0.91 g, 31.8
mmol) to the title product in free base form and isolated as a gum. The gum was dissolved in 30ml of acetone, excess ethereal hydrogen chloride was added and the mixture was evaporated to a dry solid. This solid was resuspended in a mixture of 30ml ethyl acetate and 5ml acetone to give the title product in purified form (0.90g). Melting point 162−166
℃. Analysis: C ₂₆ H ₃₁ O ₂ N ₃ F ₂・HCl・0.75, as H ₂ O Calculated value: C, 61.77; H, 6.72; N, 8.31 Actual value: C, 61.72; H, 6.44; N, 8.02 Reference Example 8 3-(4-chloro-1-butyl)-2,3-dihydro-2-benz[d]oxazolone 2,3-dihydro-2 by the procedure of Reference Example 1
-Benz[d]oxazolone (Aldrich Chemical, "2-benzoxazolinone", 5 g, 0.037 mole) was converted to the title product. The product was isolated by filtration of the reaction mixture to remove salts and vacuum evaporation to an oil. The oil was extracted with hexane and further dried by vacuum evaporation (0.8
g). Example 7 (±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2,3-dihydro-2-benz[d]oxazolon-3-yl)-1-butyl] -2, 3, 4, 4a, 5, 9b-hexahydro-4a, 9b-trans-1H-pyrido [4, 3
-b] Indole Hydrochloride According to the procedure of Example 1, the chlorobutyl compound (0.79 g, 3.5 mmol) of the previous example was prepared (±)
-8-Fluoro-5-(4-fluorophenyl)-
2.3.4.4a.5.9b-hexahydro-4a.
9b-trans-1H-pyridindole (500mg,
1.75 mmol). The reaction mixture was filtered and the filtrate was evaporated to obtain the first gum. This first gum was chromatographed on silica gel using ethyl acetate as eluent and TLC testing.
The clear product fractions were combined and the free base form of the title product was isolated as a second gum by vacuum evaporation. This second gum was dissolved in ether and excess ethereal hydrogen chloride was added. The resulting slurry was evaporated to give the title product as a solid [0.72g, Rf0.6 (ethyl acetate)]. Analysis: _C23H27O2N3F2・_HCl・_0.5H2O Calculated value _: C, 64.55; H, 5.56; _N , 8.06 Actual value: C, 64.20; H, 5.02; N _, 8.03 Reference Example 9 2-(4-acetylpiperazino)ethanol 2-piperazinoethanol (7.81 g, 60 mmol) and triethylamine (8.36 ml, 66 mmol) are dissolved in 100 ml of methylene chloride and 0-
Cooled to 5°C. Acetyl chloride (4.28 ml, 60 mmol) in 20 ml of methylene chloride was added and the reaction mixture was warmed to room temperature and held for 2 hours before evaporation in vacuo to give a dry solid. This solid was triturated with 4 parts of warm ether. The triturates were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to give 2-(4-acetylpiperazino)ethanol as an oil [7.5 g,
Free of triethylamine and triethylamine hydrochloride according to pnmy assay; Rf0.3 (methanol/10% acetic acid)]. Reference example 10 2-(4-acetylpiperazino)ethyl chloride Dissolve 2-(4-acetylpiperazino)ethanol (3.0g) in 30ml of methylene chloride,
Cooled to 0-5°C. Excess thionyl chloride (10
ml) was added dropwise. Some rubber and solid sedimentation was observed. The reaction mixture was then refluxed for 90 minutes, during which time the precipitated material redissolved. The mixture was evaporated to dryness in vacuo. The rubber thus obtained was dissolved in 100 ml of acetone, and insoluble matter was removed by filtration. Evaporation of the acetone filtrate gave an oil that was crystallized from 1:2 ethanol:ethyl acetate and ether to yield purified 2-(4-acetylpiperazino)ethyl chloride. It was done. Example 8 (±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-acetylpiperazino)
ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,
3-b] Indolebis-maleic acid hydrogen salt (±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H -pyrid [4.3-
b] Indole (1.00 g, 3.50 mmol), 2-(4-acetylpiverazino)ethyl chloride (0.885
g, 3.90 mmol) and triethylamine (1.09 ml, 7.80 mmol) were combined in 75 ml of absolute ethanol and refluxed for 2 hours. The reaction mixture was then cooled to room temperature and evaporated to dryness in vacuo. partitioning the residue between water and ether;
The aqueous layer was extracted with 2 portions of fresh ether. The combined ether layers were dried over anhydrous magnesium sulfate, filtered and evaporated to give a first crop of product. The first aqueous layer was made basic with 10% sodium hydroxide and extracted with two portions of fresh ether. The combined, dried ether extracts were similarly dried to give a second crop of product and pumped under high vacuum to remove the triethylamine adhering to the outside. The first and second crops of product were combined and chromatographed on 30 g of silica gel using 1:1 ethyl acetate:methanol as eluent. The clear product fractions are combined and evaporated to give
The title product was obtained as the free base (gum).
The free base was dissolved in acetone and excess maleic acid was added. The title product crystallizes to give two crops which, when combined, are
Recrystallized from acetonitrile/methanol.
Yield: 428 mg (melting point 203.5-204.5°C, m/e440). Analysis: Calculated value as _C25H30ON4F2・_2C4H4O4 : C, _58.92 ; H, _5.69 ; N, 8.33 Actual value: C _, 58.32 _{; H} , 5.60; N, 8.16 Example 9 (+)-8-Fluoro-5-(4-fluorophenyl)-2-[2-(4-acetylpiperazino)
ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,
3-b] Indolebis-maleic acid hydrogen salt (+)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-pyrido [4.3-b] Indole hydrochloride (526 mg, 1.63 mmol) was converted to the free base according to the method of Example 3 and 2-(4-acetylpiperazino)ethyl chloride ( 407 mg, 1.80 mmol) and triethylamine (0.50 ml, 3.6 mmol). After refluxing for 3 hours, the title product was collected, purified, converted to salt form and recrystallized according to the steps of the previous example. Yield: 340 mg [melting point 195-196°C, [Alpha] ²⁵ _D = 10.6 (C = 0.5,
methanol), m/e440]. Analysis: Calculated value as C ₂₅ H ₃₀ N ₄ OF ₂・2C ₄ H ₄ O ₄ : C, 58.92; H, 5.69; N, 8.33 Actual value: C, 58.47; H, 5.44; N, 8.20 Reference example 11 1-Benzyl-4-(4-chlorobutyryl)piperazine N-benzylpiperazine (1.0 g, 5.7 mmol) and triethylamine (1.17 ml, 8.5 mmol) were combined in 20 ml of methylene chloride. 4-chlorovaleryl chloride (0.945 ml, 8.5 mmol) in 10 ml of methylene chloride was added dropwise over 20 minutes,
The reaction mixture was stirred at room temperature for 16 hours. Water (20ml) was then added and the organic layer was dried (anhydrous magnesium sulphate) and evaporated in vacuo to give a rubber. This rubber was washed with ethyl acetate eluent and TLC.
Chromatographed on silica gel using test. The clear product fractions were combined and evaporated to give the title product as a gum [920 mg, Rf0.5
(Ethyl acetate)〕. Reference example 12 (±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(4-benzylpiperazinecarbonyl)-1-propyl]-2.3.4.4a.
5・9b-hexahydro-4a・9b-trans-
1H-pyrido[4.3-b]indole bis-hydrochloride By the method of Example 1, (±)-8-fluoro-5-(4-fluorophenyl)2.3.4.
4a, 5, 9b-hexahydro-4a, 9b-trans-1H-pyrido [4, 3-b] indole (625
mg, 2.2 mmol) with 1-benzyl-4-(4-chlorobutyryl)piverazine to give the title product in the form of the chromatographed free base. The base was dissolved in acetone, converted to the bis-hydrochloride salt with excess ethereal hydrogen chloride, and the title product was isolated by evaporation to dryness and resuspension in ether. 0.485g, m/e530]. Analysis _{: C32H36ON4F2}・_{2HCl ・ 2.25H2O} Calculated value: C, 59.67; H, 6.52; N, 8.69 Actual value: C, 59.55; H, 6.53; N, 8.68 Example 10 (±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(4-benzylpiverazino)-
1-Butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole tris hydrochloride (±)-8-fluoro-5-( 4-fluorophenyl)-2-[3-(4-benzylpiverazino carbonyl)-1-propyl]-2.3.4.4a.
5,9b-hexahydro-4a,9b-trans-1H
-Pyrido[4.3-b]indole bis-hydrochloride (1 g) was dissolved in 30 ml of tetrahydrofuran. Lithium aluminum hydride (approximately 9 equivalents) was added in portions and hydrogen evolution was observed during most of the addition. After stirring for an additional 30 minutes at room temperature, excess Glauber's salt (sodium sulfate decahydrate) was added and the mixture was stirred for an additional 10 minutes. The reaction mixture was filtered and washed with tetrahydrofuran and the combined filtrate and washings were evaporated to dryness. The rubber thus obtained was dissolved in acetone and converted into the hydrochloride by adding ethereal hydrogen chloride. The resulting slurry was dried, resuspended in a mixture of 30 ml acetone and 10 ml methanol, and filtered to give the title product [120 mg, Rf0.2 (methanol);
m/e516]. Analysis: _Calculated value _{as C32H38N4F2.3HCl :} C, 61.39; H, 6.59; N, 8.95 Actual value: C, 61.26; H, 6.68; N, 8.78 Example 11 (±)-8 -Fluoro-5-(4-fluorophenyl)-2-(4-piverazino-1-butyl)-
2, 3, 4, 4a, 5, 9b-hexahydro-
4a・9b-trans-1H-pyrido [4・3-
b] Indole tris-hydrochloride (±)-8-fluoro-5- from the previous example
(4-fluorophenyl)-2-[4-(4-benzylpiperazino)-1-butyl]-2.3.4.4a.
5,9b-hexahydro-4a,9b-trans-1H
The entire batch of -pyrido[4.3-b]indole tris-hydrochloride was dissolved in 10 ml of ethanol containing 3 drops of concentrated hydrochloric acid. Hydrogenation catalyst (10%
Pd/c, 250 mg) was added and the mixture was hydrogenated at 50 psi and 40° C. for 6 hours. The catalyst was recovered by filtration and ethanol washing. The combined filtrate and washings were evaporated to a gum. This rubber is dissolved in a minimum amount of methanol and then in acetone.
Crystallization was performed by adding 100 ml and stirring for 30 minutes. The yield of the title product as the trihydrate was 0.3 g (melting point 229-232°C). Example 12 (±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-acetylpiverazino)-
1-Butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-hexahydro-4a,9b-
trans-1H-pyrido[4,3-b]indole bis-hydrochloride (±)-8-fluoro-5-(4-fluorophenyl)-2-(4-piperazino-1-butyl)-
2.3.4.4a.5.9b-hexahydro-4a.
9b-trans-1H-pyrido[4.3-b]indoletris-hydrochloride trihydrate (377 mg, 0.64 mmol) and triethylamine (0.68 ml, 4.92
mmol) was dissolved in 8 ml of methylene chloride. Acetyl chloride (0.055
ml, 0.77 mmol) dropwise over 20 minutes,
The mixture was then stirred at room temperature overnight. Water (12ml) was then added to the reaction mixture. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to a gum. This gum is dissolved in ether, converted to the hydrochloride salt by addition of ethereal hydrogen chloride, the mixture is evaporated to dryness, and the residue is resuspended in acetone, from which the title product is obtained. was obtained as a hygroscopic solid (150 mg). Melting point 211-215℃. Analysis: C ₂₇ H ₃₄ N ₄ OF ₂・2HCl・2H ₂ O Calculated value: C, 56.15; H, 6.92; N, 9.69 Actual value: C, 56.31; H, 7.24; N, 9.75 Reference example 13 ( ±)-8-fluoro-5-(4-fluorophenyl)-2-(3-piverazinocarbonyl-1-
propyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole bis-hydrochloride (±)-8-fluoro from Reference Example 12 -5-(4
-fluorophenyl)-2-[3-(4-benzylpiperazinocarbonyl)-1-propyl]-2.
3.4.4a.5.9b-hexahydro-4a.9b-
trans-1H-pyrido[4.3-b]indolbis hydrochloride (1 g) at 45 psi and 40°C.
Hydrogenation was carried out for 16 hours in 20 ml of ethanol containing 6 drops of concentrated hydrochloric acid in the presence of 300 mg of 10% Pd/c catalyst. The catalyst was recovered by filtration and the mother liquor was evaporated to give a rubber. This rubber was crystallized by slurrying it with acetone [0.640 g;
(KBr) 1470, 1508, 1639, 1733, 3390cm ^-1 ;
m/e440]. Analysis: C ₂₅ H ₃₀ N ₄ OF ₂・2HCl・3H ₂ O Calculated value: C, 52.91; H, 6.69; N, 9.87 Actual value: C, 52.61; H, 6.53; N, 9.93 Reference example 14 ( ±)-8-Fluoro-5-(4-fluorophenyl)-2-[3-(4-acetylpiperazinocarbonyl)-1-propyl]-2.3.4.4a.
5・9b-hexahydro-4a・9b-trans-
1H-pyrido[4.3-b]indole hydrochloride The piperazinocarbonyl compound of the two previous examples (500 mg, 1.14
acetyl chloride (0.089 ml, 1.25 mmol) and triethylamine (0.628 ml, 4.5 mmol) were reacted by the method of Example 12.
The crude product (isolated from methylene chloride after quenching with water) was chromatographed on silica gel using 1:1 methanol:ethyl acetate eluent and TLC testing [Rf0.2 (1:1 methanol:
Ethyl acetate)〕. The clear, product-containing fractions were combined and evaporated to dryness. The gum thus obtained was dissolved in ether, converted to the hydrochloride salt by addition of ethereal hydrogen chloride, and evaporated to give a solid. This solid was resuspended in 10 ml of acetone and filtered to give the title product (50 mg, mp
220−223℃). Analysis: C ₂₇ H ₃₂ N ₄ O ₂ F・HCl・0.75H ₂ O Calculated value: C, 60.90; H, 6.54; N, 10.52 Actual value: C, 60.96; H, 6.44; N, 10.32 Reference example 15 1-(4-chloro-1-butyl)-2,3-indolinedione Sodium hydride (50% dispersion in oil, 1.63 g, 34 mmol) under dry nitrogen was washed with 50 ml of ether. Removed oil. The ether was separated by decantation. dimethylformamide (25ml),
Added to ether moistened sodium hydride. 2,3-indolinedione (isatin, 5 g, 34 mmol) and 1,4-dichlorobutane (21.6 g, 18.6 ml, 0.17
A solution of 1 mmol) was added dropwise over a period of 1 hour while maintaining the temperature at 25-28°C. The solution thus obtained was stirred for 1 hour at room temperature. The reaction mixture was filtered and the filtrate was evaporated to 30ml and diluted with 50ml of methylene chloride. The resulting mixture was filtered again, the filtrate was evaporated to dryness, and the residue was slurried in 200 ml of ether. The ether was decanted from the drum and evaporated to give the title product [830mg, Rf0.55 1:1 ethyl acetate:hexanes]. Example 13 (±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2,3-indolinedione-1-yl)-1-butyl]-2.3.4. 4a・
5・9b-hexahydro-4a・9b-trans-
1H-pyrido[4,3-b]indole hydrochloride 1-(4-chloro-1-butyl)-2,3-indolinedione (830 mg, 3.5 mmol), (±)-8
-Fluoro-5-(4-fluorophenyl)-2.
3.4.4a.5.9b-hexahydro-4a.9b-
trans-1H-pyrido[4.3-b]indole (500 mg, 1.75 mmol), anhydrous sodium carbonate (1.1 g, 10.4 mmol) and potassium iodide (5
mg) were combined in 3-methyl-2-butanone (20ml) and refluxed for 16 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between 50 ml methylene chloride and 50 ml water. The aqueous phase was washed with an additional 50ml of methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to give a gum. This rubber was treated with tlc using ethyl acetate.
Chromatographed on silica gel. The clear, product-containing fractions were combined and evaporated to dryness. The residue was triturated with ethereal hydrogen chloride to give the title product [226
mg, ir (KBr) 1477, 1520, 1623, 1724, 3390cm
^-1 〕. Reference Example 16 3-Benzyl-2,4-imidazolidinedione Hydantoin (2,4-imidazolidinedione; 25 g, 0.25 mol) was dissolved in 1 liter of 90% ethanol. Add potassium hydroxide (15 g, 0.27 mol) in 125 ml of ethanol and bring the mixture to 16
Stir the time. The potassium salt was recovered by filtration and dried under reduced pressure at 80°C [25.2g, mp
271-2℃ (decomposition)]. Potassium salt (5.5 g, 0.04 mol) and benzyl bromide (17.1 g, 11.9 ml, 0.10 mol) were combined with 40 ml of dimethylformamide and the mixture was heated at room temperature.
After stirring for 16 hours, the mixture was refluxed for 4 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to an oil. This oil was dissolved in chloroform. The chloroform solution was washed with water, then saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to a solid. Trituration of this solid with ether gave the title product (3.0 g, mp 139-140°C, m/e 190). Reference Example 17 1-Benzyl-1-(4-bromo-1-butyl)-2,4-imidazolidinedione The benzylimidazoline of Reference Example 16 (1.9 g, 10 mmol) in 5 ml of dimethylformamide,
Slurry of sodium hydride (50% dispersion in oil)
528 mg, 11 mmol) was added dropwise and the mixture was then stirred at room temperature for 1 hour. The solution thus obtained was added dropwise to 1,4-dibromobutane (2.37 g, 11 mmol) in 10 ml of dimethylformamide. After stirring at room temperature for 16 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. This oil was chromatographed on silica gel using chloroform as eluent. Combined evaporation of the clear product fractions afforded the title product as an oil [1.4 g, pnmr ( _CDCl3 ) delta 1.6
-2.0 (m, 4H), 3.2-3.6 (m, 4H), 3.8 (s,
2H), 4.6 (s, 2H), 7.2-7.5 (m, 5H)]. Example 14 (±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-3-benzyl-2,4-imidazolidinedione-1-yl)-1-butyl]-
2, 3, 4, 4a, 5, 9b-hexahydro-
4a・9b-trans-1H-pyrido [4・3-
b] Indole hydrochloride (±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido [4,3 −
b] Indole (573 mg, 2 mmol), Reference Example 17
of bromobutylimidazolidinedione (1.3g,
4 mmol), potassium carbonate (1.3 g, 10 mmol) and potassium iodide (10 mg) were combined with 4-methyl-2-pentanone (25 ml). The mixture was stirred at room temperature for 4 days and then evaporated to an oil. This oil was dissolved in chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and reevaporated to a second oil. The second oil was chromatographed on 150 ml of silica gel. Less polar by-products were removed by elution with chloroform. The product was then eluted from the column using 99:1 chloroform:methanol. The clear product fractions were combined and evaporated to give the free base form (880 mg).
The free base was dissolved in ether and precipitated as the hygroscopic hydrochloride salt upon addition of ethereal hydrogen chloride (560 mg). Recrystallization from ethyl acetate followed by recrystallization from chloroform/ethyl acetate gave the title product in non-hygroscopic form [250 mg, mp 191-194°C (decomposition)] Analysis: C ₃₁ H ₃₂ Calculated value as N ₄ O ₂ F ₂ HCl: C, 65.66; H, 5.86; N, 9.88 Actual value: C, 65.34; H, 5.73; N, 10.09 Reference example 18 2-(4-chloro-1- Butyl)-3(2H)-benz[d]isothiazolone 1,1-dioxide Satucalin sodium (5.6 g, 0.027 mol) and 1,4-dichlorobutane (14.9 ml, 0.135 mol) were dissolved in 100 ml of dimethylformamide. and heated on a steam bath for 4 hours. The reaction mixture was evaporated in vacuo to an oil and the oil was extracted with 100ml hexane. Residual hexane was removed from the remaining oil by vacuum evaporation to give the title product (956 mg). Example 15 (±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[1,1-dioxo-3
(2H)-benz[e]isothiazolon-2-yl]-1-butyl]-2, 3, 4, 4a, 5, 9b
-trans-1H-pyrido[4,3-b]indole hydrochloride Title compound of Reference Example 18 (956 mg, 3.5 mmol), (±)-8-fluoro-5-(4-fluorophenyl)-2,3・4.4a.5.9b-hexahydro-4a.9b-trans-1H-pyrido [4.3-
b] Indole (500 mg, 1.75 mmol), anhydrous sodium carbonate (1.1 g, 10.5 mmol) and potassium iodide (5 mg) were reacted in 3-methyl-2-butanone (20 ml) by the method of Example 1. I let it happen. After refluxing for 16 hours, the reaction mixture was evaporated to a gum and the gum was evaporated 1:1 as eluent.
Chromatographed on silica gel using methylene chloride:ethyl acetate. tlc this column
combined single component product fractions;
A second rubber was obtained by evaporation. The second rubber is dissolved in ether and acidified with ethereal hydrogen chloride;
The resulting suspension was then evaporated to give the title product [339 mg; Rf 0.45 (1:1 methylene chloride:ethyl acetate)]. Analysis: _Calculated value _{as C28H27N3O3SF2}・_HCl・_H2O : C, 58.18; _H , 5.23; N, 7.26 Actual value: C, 57.90; H, 5.21; N, 7.07 Example 16 (±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2,3-dihydro-2,3
(1H)-isoindoldione-2-yl)-1
-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole hydrochloride N-(4 -Bromo-
1-Butyl)phthalimide (0.985 g, 3.5 mmol) was converted to the title product. The crude product isolated from the water/methylene chloride partition was prepared as eluent at 1:
Chromatographed on silica gel using ethyl 1 acetate:methylene chloride and using TLC testing. The clear product fractions were combined and evaporated to a gum. The gum was dissolved in ether and converted to the hydrochloride salt by addition of ethereal hydrogen chloride. The suspension thus obtained was dried and crystallized from the residue and acetone to give the title product [425 mg,
Melting point 169-171°C, Rf 0.55 (1:1 ethyl acetate:methylene chloride)]. Analysis: _Calculated value _{as C29H27N3O2F2}・_HCl・_H2O : C, _64.26 ; H, 5.57; N, 7.75 Actual value: C, 64.01; H, 5.14; N, 7.64 Reference example 19 3-(4-Chloro-1-butyl)-2,4-thiazolidinedione 2,4-thiazolidinedione (8 g, 0.068 mol) was converted to the title product by the procedure of Reference Example 1. The reaction mixture was filtered and evaporated to an oil. The oil is triturated with methylene chloride, the solids are removed by filtration, and the filtrate is reevaporated.
The desired product was obtained as an oil [Rf0.2 (4:
1 ethyl acetate:methanol)]. Example 17 (±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2,4-thiazolidinedione-3-yl)-1-butyl]-2,3,4.
4a, 5, 9b-hexahydro-4a, 9b-trans-1H-pyrido [4, 3-b] indole
Hydrochloride According to the process of Example 1, chlorobutylthiazolidine (543 mg, 2.62 mmol) of Reference Example 19 was
The title compound was converted to the crude free base form. The crude base was purified with ethanol as eluent and
Chromatographed on silica gel using TLC test. The clear product fractions were combined and evaporated to give a gum. This rubber was dissolved in ether and acidified with ethereal hydrogen chloride.
A solid was obtained by evaporation and reslurried in hexane to give the title product (479 mg, melting point not determined due to hygroscopic nature). Analysis: _{C24H25F2O2N3S}・HCl・_1.2H2O Calculated value: _C , 55.90; H, 5.51; _N , 8.15 Actual value _: C _, 55.37; H, 4.96; N, 8.01 Example 18 (±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(2,4-imidazolidinedione-1-yl)ethyl]-2.3.4.4a.
5・9b-hexahydro-4a・9b-trans-
1H-pyrido[4.3-b]indole By the process of Example 1, (±)-8-fluoro-5-(4-fluorophenyl)-2.3.4.
4a, 5, 9b-hexahydro-4a, 9b-trans-1H-pyrido [4, 3-b] indole (573
mg, 2 mmol) to 3-(2-bromoethyl)-
Reaction with 2,4-imidazolidinedione (828 mg, 4 mmol) formed the title product.
The reaction mixture was filtered, washed with chloroform and the combined filtrates were evaporated to dryness. The solid residue was chromatographed on 100 ml of silica gel using ethyl acetate eluent and TLC examination. The clear product fractions were combined and evaporated to dryness, and the residue was recrystallized from chloroform/hexane to give the title product [444 mg, mp
195-197℃ (decomposition)]. For analysis, an additional 200 mg was recrystallized from methanol. [180mg, melting point
191-193℃ (decomposition)]. Analysis: _Calculated value _{as C22H22F2N4O2 :} C, 64.07; H, 5.38; N, 13.58 Actual value: C, 63.72; _H , 5.47; N, 13.45 Reference example 20 3-(3- Bromo-1-propyl)-2,4-imidazolidinedione The potassium salt of 2,4-imidazolidinedione (hydantoin; 5.5 g, 0.04 mol; prepared as in Example 29) was dissolved in dimethylformamide 50
1,3-dibromopropane in ml (14.3ml, 0.14
mol) at room temperature for 16 hours and then for 2 hours under reflux. The reaction mixture was filtered, evaporated to dryness and the residue was recrystallized from isopropyl alcohol (950 mg, mp 103-106 °C,
m/e222/220). Example 19 (±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(2,4-imidazolidinedione-3-yl)-1-propyl]-2,3.
4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole methanesulfonate (±)-8-fluoro-5-(4-fluorophenyl)-2・3.4.4a.5.9b-hexahydro-4a.9b-trans-1H-pyrido [4.3-
b] indole (573 mg, 2 mmol) and 3
-(3-bromo-1-propyl)-2,4-imidazolidinedione (884 mg, 4 mmol), sodium carbonate (1.06 g, 10 mmol), potassium iodide (10 mg) and 4-methyl-2-pentanone 10 ml
were combined and the mixture was heated to 80-90°C for 5 hours. At this point, a tlc check (9:1 chloroform:methanol) showed that the pyridindole starting material was completely consumed. The reaction mixture was filtered and the filtrate was evaporated to dryness. Dissolve the residue in ethanol, add ether to cloud point,
After standing for 16 hours, filtering and evaporating the filtrate to dryness, the title product was obtained in the free base form (900
mg). The free base was dissolved in ethanol. Two equivalents of sulfonic acid were added. On standing, the title product (methane sulfonate) crystallized and was recovered by filtration [530 mg, mp 246-249°C].
(disassembly); m/e426]. Analysis _{: C23H24N4O2F2 ・ CH4SO3 ・ 0.33H2O Calculated} value: C, 54.54; H, 5.47; N, 10.60 Actual value: C, 54.48; H, 5.33 _; N , 10.66 Reference Example 21 3-(6-bromo-1-hexyl)-2,4-imidazolidinedione 1,6-dibromohexane (24.2 g, 0.10 mol) was reacted according to the process of Reference Example 20. , the title product was formed. The reaction mixture was filtered, the filtrate was evaporated to an oil, and the oil was dissolved in chloroform. Washed with chloroform solution, water then saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to a second oil which was crystallized from ether/hexanes. (3.7 g, melting point 84-86°C, m/e 264/262. Example 20 (±)-8-fluoro-5-(4-fluorophenyl)-2-[6-(2,4-imidazolizidine) dion-3-yl)-1-hexyl]-2.3.
4.4a.5.9b-Hexahydro-1H-pyrido[4.3-b]indole hydrochloride Example 37, except that the eluent for chromatography was 19:1 chloroform:methanol.
3-(6-bromo-1-hexyl)-2,4-imidazolidinedione (1.05 g,
0.04 mol) was reacted to form the title product. The free base was isolated as an oil from the clear column fractions. The base was dissolved in ethanol and ethanolic hydrogen chloride was added to precipitate the hydrochloride salt. Recrystallization twice from ethanol gave the title product in purified form (220 mg, mp 168-171°C). Analysis _{: C26H30F2N4O2}・_HCl・_0.5H2O Calculated value _: C, 60.75; H, 6.28; _N , 10.90 Actual value: C, 60.47; H, 5.90; N, 10.82

Claims (1)

[Claims] 1 formula [where n is 2 to 6, and R ¹ is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or [ The (+) enantiomer, the mixture of (+) and (-) enantiomers, or the (±) racemate of the formula
4a.9b-trans-hexahydro-1H-pyridoindole derivative or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R ¹ is [Formula]. 3. The compound according to claim 1, wherein R ¹ is [Formula]. 4. The compound according to claim 1, wherein R ¹ is [Formula]. 5. The compound according to claim 1, wherein R ¹ is [Formula]. 6. The compound according to claim 1, wherein R ¹ is [Formula].